Method of increasing or maintaining the reproductive performance of sows

ABSTRACT

The present invention relates to methods and feed compositions for increasing or maintaining the reproductive performance of sows. More particularly, the present invention relates to methods of increasing or maintaining the reproductive performance of sows by administering a biologically active compound during lactation, and food compositions comprising said biologically active compound for the purposes of increasing or maintaining the reproductive performance of sows. The present invention also relates to a method of increasing or maintaining ovarian function in sows.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 61/408,101 filed 2010 Oct. 29, which isincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to methods and feed compositions forincreasing or maintaining the reproductive performance of sows. Moreparticularly, the present invention relates to methods of increasing ormaintaining the reproductive performance of sows by administering abiologically active compound during lactation, and food compositionscomprising said biologically active compound for the purposes ofincreasing or maintaining the reproductive performance of sows. Thepresent invention also relates to a method of increasing or maintainingovarian function in sows.

BACKGROUND OF THE INVENTION

Sow productivity has traditionally been defined as the number of progenypigs weaned per sow per year. However, the length of time that sowsremain productive within commercial operations also plays a major factorin their profitability and economic success. Producers are financiallyrewarded for having sows with an improved productive lifetime becausethe initial cost of the replacement gilt and associated developmentexpenses to be spread across a greater number of piglets produced duringthe sow's lifetime.

Current sow culling rates are excessive and often sows are removed fromthe breeding population before reaching their breakeven parity. Thissituation can affect overall profitability. Reasons for culling sows canbe attributed to genetics, reproduction, nutrition, environment, andmanagement. However, premature culling of breeding sows tends to fallinto two distinct categories:

-   -   Very early culling of gilts and parity 1 sows on the basis of        reproductive failure and locomotor problems.    -   Culling around parities 3-5 for poor reproductive performance.

Therefore, reproductive failure is accepted to be the largest reason forthe culling of primiparous sows.

Sow productive lifetime or length of productive life is typicallymeasured several ways, including days of age from birth to culling, lifefrom entry into the breeding population through culling, and the numberof successful parities completed. Currently, the Australian industryaverage is predicted to be 30-40 pigs weaned/lifetime which is wellbelow the potential to produce at least 80-90 pigs weaned per sow perlifetime. Similar poor sow reproductive performance is also reported inmost other major pig producing countries. Therefore, pig producers areconstantly looking for ways to increase sow performance and productivelife.

For many years it has been thought by most within the research communitythat the limitation to improved reproduction is simply a matter ofimproving the implementation of existing knowledge to producers.However, with national herd statistics showing that reproduction is notimproving, pig producers are highlighting that this approach must becombined with both large scale studies that report on longevity andresearch into the fundamental nutritional and management requirements,in particular because of today's genetically lean genotypes.

Studies have shown that modification of the gilt's fat reserves as sheenters the breeding population through protein restriction or increasedfeeding levels rarely demonstrates an improvement in reproductiveperformance over several parities. Likewise, no improvement inreproductive performance has been seen by increasing fatness in sows fedhigh energy diets during successive pregnancies. Increasing proteinintake in gestation and lactation has also been recently studied inyoung sows. While litter size born subsequent to sows being fed highprotein diets during the first lactation was positively correlated withlactation lysine intake, no benefit of high protein intake on weaning toconception interval was observed.

Accordingly, there exists an ongoing need to develop new and effectivemethods for increasing reproductive performance in sows and thereforesow lifetime productivity.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to a method ofincreasing or maintaining the reproductive performance of a sowcomprising administering an effective amount of a β-agonist duringlactation.

Another aspect of the present invention is directed to a method ofincreasing or maintaining the reproductive performance of a sowcomprising administering an effective amount of a β-agonist duringlactation, wherein the β-agonist is ractopamine.

Another aspect of the present invention is directed to a method ofincreasing or maintaining the reproductive performance of a sowpopulation comprising administering an effective amount of a β-agonistduring lactation to each sow within said population.

Yet another aspect of the present invention is directed to a method ofincreasing or maintaining the reproductive performance of a sowpopulation comprising administering an effective amount of a β-agonistduring lactation to each sow within said population, wherein theβ-agonist is ractopamine.

In another aspect the present invention is directed to a method forincreasing or maintaining ovarian function in a sow comprisingadministering an effective amount of a β-agonist during lactation.

In yet another aspect the present invention is directed to a method forincreasing or maintaining ovarian function in a sow comprisingadministering an effective amount of a β-agonist during lactation,wherein the β-agonist is ractopamine.

Another aspect of the present invention is directed to a method ofdecreasing the weaning to oestrus interval of a sow comprisingadministering an effective amount of a β-agonist during lactation.

A still further aspect of the present invention is directed to a methodof decreasing the weaning to oestrus interval of a sow comprisingadministering an effective amount of a β-agonist during lactation,wherein the β-agonist is ractopamine.

A further aspect of the present invention is directed to a method ofdecreasing the weaning to oestrus interval of a sow comprisingsupplementing the lactation diet with an effective amount of ractopaminefrom day 1 of lactation until weaning, wherein the lactation diet issupplemented with between 5 and 20 ppm of ractopamine/unit of diet.

A still further aspect of the present invention is directed to a methodof decreasing the weaning to oestrus interval of a sow comprisingsupplementing the lactation diet with an effective amount of ractopaminefrom day 1 of lactation until weaning, wherein the lactation diet issupplemented with 10 ppm of ractopamine/unit of diet from days 1 to 13of lactation and 20 ppm of ractopamine/unit of diet from day 14 oflactation until weaning.

In a further aspect the present invention is directed to a method ofincreasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising administering an effectiveamount of a β-agonist during lactation, to each sow within saidpopulation.

In yet another aspect the present invention is directed to a method ofincreasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising administering an effectiveamount of a β-agonist during lactation, to each sow within saidpopulation, wherein the β-agonist is ractopamine.

In a further aspect the present invention is directed to a method ofincreasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising supplementing the lactation dietwith an effective amount of a β-agonist from day 1 of lactation untilweaning.

In a still further aspect the present invention is directed to a methodof increasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising supplementing the lactation dietwith an effective amount of a β-agonist from day 1 of lactation untilweaning, wherein the β-agonist is ractopamine.

A still further aspect of the present invention is directed to a methodof increasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising supplementing the lactation dietof each sow within said population with an effective amount ofractopamine from day 1 of lactation until weaning, wherein the lactationdiet is supplemented with between 5 and 20 ppm of ractopamine/unit ofdiet.

A still further aspect of the present invention is directed to a methodof increasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising supplementing the lactation dietof each sow within said population with an effective amount ofractopamine from day 1 of lactation until weaning, wherein the lactationdiet is supplemented with 10 ppm of ractopamine/unit of diet from days 1to 13 of lactation and 20 ppm of ractopamine/unit of diet from day 14 oflactation until weaning.

A further aspect of the present invention is directed to a method ofincreasing or maintaining the number of progeny pigs weaned per sow insubsequent pregnancies comprising administering an effective amount of aβ-agonist during lactation.

A still further aspect of the present invention is directed to a methodof increasing or maintaining the number of progeny pigs weaned per sowin subsequent pregnancies comprising administering an effective amountof a β-agonist during lactation, wherein the β-agonist is ractopamine.

A further aspect of the present invention is directed to a method ofincreasing or maintaining the number of progeny pigs weaned per sowpopulation in subsequent pregnancies comprising administering aneffective amount of a β-agonist during lactation, to each sow withinsaid population.

A still further aspect of the present invention is directed to a methodof increasing or maintaining the number of progeny pigs weaned per sowpopulation in subsequent pregnancies comprising administering aneffective amount of a β-agonist during lactation, to each sow withinsaid population, wherein the β-agonist is ractopamine.

A further aspect of the present invention provides a method forsynchronizing mating and/or artificial insemination of a sow populationcomprising administering an effective amount of a β-agonist duringlactation, to each sow within said population.

A still further aspect of the present invention provides a method forsynchronizing mating and/or artificial insemination of a sow populationcomprising administering an effective amount of a β-agonist duringlactation, to each sow within said population, wherein said β-agonist isractopamine.

In a further aspect the present invention provides a method forincreasing the number of sows within a sow population which undergomating and/or artificial insemination comprising administering aneffective amount of a β-agonist during lactation, to each sow withinsaid population.

In another aspect the present invention provides a method for increasingthe number of sows within a sow population which undergo mating and/orartificial insemination comprising administering an effective amount ofa β-agonist during lactation, to each sow within said population,wherein said β-agonist is ractopamine.

In yet, a further aspect the present invention provides a method forincreasing the number of times a sow and/or sow population undergoesmating and/or artificial insemination per year comprising administeringan effective amount of a β-agonist during lactation, to each sow withinsaid population. Preferably, said β-agonist is ractopamine.

In another aspect the present invention provides a method for increasingthe number of times a sow and/or sow population undergoes mating and/orartificial insemination per year comprising administering an effectiveamount of a β-agonist during lactation, to each sow within a population,wherein said β-agonist is ractopamine.

In a further aspect the present invention is directed to a feedcomposition comprising an effective amount of a β-agonist wherein saideffective amount increases or maintains the reproductive performance ofa sow.

In a still further aspect the present invention is directed to a feedcomposition comprising an effective amount of a β-agonist wherein saideffective amount increases or maintains the reproductive performance ofa sow and wherein said β-agonist is ractopamine.

DETAILED DESCRIPTION OF THE INVENTION

As stated hereinbefore, reproductive failure is one of the largestreasons for culling of primiparous sows. The present invention ispredicated on the discovery that administration of the β-agonistractopamine to sows during lactation reduces maternal weight loss andimproves subsequent reproductive performance.

Accordingly, one aspect of the present invention is directed to a methodof increasing or maintaining the reproductive performance of a sowcomprising administering an effective amount of a β-agonist duringlactation. Preferably, said β-agonist is ractopamine.

Reference to a “sow” should be understood as a reference to a female pigwhich has been mated one or more times. Reference to a “gilt” isreference to a female pig which has not yet been mated or has just beenmated but which has not yet produced progeny pigs. Reference to a “pig”should be understood as a reference to all pigs, for example, gilts,sows, hogs, boars and barrows. The skilled person will be well awarethat in the context of the present invention the term “pig” issynonymous with swine. A “progeny pig” or “piglet” refers to theoffspring produced by a sow.

As stated hereinbefore, sow productivity is traditionally defined as thenumber of progeny pigs weaned per sow per year. However, the length oftime that sows remain productive within commercial operations also playsa major factor in their profitability and economic success. This factordepends on the number of successful parities completed. Accordingly,reference to reproductive performance in the context of the presentinvention should be understood as reference to both the number ofprogeny pigs weaned per sow per year, and reference to the number ofprogeny pigs weaned per lifetime of a sow in the breeding herd (PW/LF).A number of factors can play a part in the reproductive performance ofan individual sow, for example, but not limited to, the age and weightof the individual sow. Accordingly, reference to reproductiveperformance in the context of the present invention should also beunderstood as reference to the number of progeny pigs weaned, per sowpopulation, per year.

Without limiting the present invention to any one theory or mode ofaction, it is thought to be the excessive mobilisation of body storesand in particular body protein during lactation that ultimately resultsin poor body condition at weaning and increases the likelihood ofculling due to subsequent reproductive failure. Accordingly, referenceto an increase in reproductive performance should be understood asreference to both an increase in the number of progeny pigs weaned persow and/or sow population per year as well as reference to an increasein the number of progeny pigs weaned in subsequent pregnancies per sowand/or sow population as compared to a control sow and/or controlpopulation in which the β-agonist was not administered. Reference tomaintaining reproductive performance in the context of the presentinvention should be understood to refer to the maintenance of theinitial reproductive performance of a sow and/or sow population insubsequent pregnancies. Reference to the “initial reproductiveperformance” of a sow should be understood as reference to the sow'sreproductive performance as a gilt.

Reference to a “control sow” should be understood as reference to a sowwhich has not received treatment in accordance with the method of theinvention. Reference to subsequent pregnancies should be understood asreference to the next litter of progeny pigs produced by the sow.

It has been demonstrated that mobilisation of more than 9-12% of a sow'sprotein mass present at parturition results in a reduction in the numberand size of ovarian follicles at weaning, follicular fluid volume andoestradiol levels, and the ability of follicular fluid to advance invitro maturation of oocytes. In other words, a compromise of endocrinesupport for follicular growth and oocyte maturation. Also withoutlimiting the present invention to any one theory or mode of action,fewer, less developed follicles being present at weaning, i.e.,inadequate ovarian function may explain why the weaning-to oestrusinterval may be extended and sometimes result in anoestrus. This hasbeen found to particularly be the case in parity 1 sows.

Accordingly, in yet another aspect the present invention is directed toa method for increasing or maintaining ovarian function in a sowcomprising administering an effective amount of a β-agonist duringlactation. Preferably the β-agonist is ractopamine.

Reference to increasing ovarian function should be understood asreference to an increase in ovarian function as compared to a controlsow in which the β-agonist was not administered. Reference tomaintaining ovarian function should be understood to refer to themaintenance of the initial ovarian function of a sow in subsequentpregnancies

As hereinbefore described, it is the failure of sows to return topostpartum oestrus which ultimately affects their reproductiveperformance. Without limiting the invention to any one theory or mode ofaction, the inventors have unexpectedly discovered that ractopamine,when fed to sows during lactation, is effective in improving the totalnumber of sows within a population which exhibit oestrus at weaning.

Accordingly, reference to increasing reproductive performance in thecontext of the present invention should therefore also be understood asreference to an increase in the number of animals within a populationwhich exhibit oestrus at weaning as compared to a control population towhich ractopamine was not administered. Accordingly, reference tomaintaining reproductive performance in the context of the presentinvention should also be understood to refer to the maintenance of thenumber of sows which exhibit oestrus at weaning in subsequentpregnancies.

Accordingly, in a further aspect the present invention is directed to amethod of increasing or maintaining the number of sows in a populationwhich return to oestrus at weaning comprising administering an effectiveamount of a β-agonist during lactation, to each sow within saidpopulation.

In a further aspect the present invention is directed to a method ofincreasing or maintaining the number of sows in a population whichreturn to oestrus at weaning comprising supplementing the lactation dietwith an effective amount of a β-agonist from day 1 of lactation untilweaning.

Preferably, said β-agonist is ractopamine.

The term oestrus is well known in the art to refer to the periodic stateof sexual excitement in the female of most mammals, excluding humans,that immediately precedes ovulation and during which the female is mostreceptive to mating. The skilled person would be well aware of the signsof oestrus and of how to determine when oestrus occurs. As used herein,the term “oestrus” refers to a sow that is receptive to mating.

While it is possible that milk can be expressed prior to parturition,without limiting the invention to any one theory or mode of action, itis the act of suckling by the progeny pigs which is the cause ofdepletion of body reserves and reproductive failure in subsequentpregnancies. Accordingly, reference to lactation in the context of thepresent invention should be understood to encompass the period followingbirth up until weaning of progeny pigs, during which milk is secreted.As used herein, it should be understood that the phrase “lactating sow”refers to a sow that has given birth to a litter of pigs and ispresently producing milk. As used herein, the term “weaning” refers tothe removal of progeny pigs from a lactating sow.

Studies have shown that it takes at least three litters before a sowprovides a positive cash flow for the producer. Accordingly, withoutlimiting the invention in any way, preferably, the increase ormaintenance is of a parity 1, 2 or 3 sow. Even more preferably, theincrease or maintenance is of a parity 1 sow.

As used herein, the phrase “parity 1 sow” refers to a sow that has hadits first litter of pigs. The phrase “parity 2 sow” refers to a sow thathas its second litter of pigs and the phrase “parity 3 sow” refers to asow that has had its third litter of pigs, and the phrase “parity 3 orgreater sow” refers to a sow that has had more than three litters ofpigs.

Without limiting the present invention to any one theory or mode ofaction, the present inventors have determined that administration of theβ-agonist ractopamine during lactation decreases the weaning to oestrusinterval (WOI) of a sow and/or sow population compared to a controlanimal and/or control population which has not been administered theβ-agonist.

Accordingly, yet another aspect of the present invention is directed toa method of decreasing the weaning to oestrus interval of a sowcomprising administering an effective amount of a β-agonist duringlactation.

In yet another aspect the present invention is directed to a method ofdecreasing the weaning to oestrus interval of a sow populationcomprising administering an effective amount of a β-agonist duringlactation to each sow within said population.

Preferably, said β-agonist is ractopamine.

Preferably following administration of the β-agonist the WOI is <15days. Even more preferably, following administration of the β-agonistthe WOI is <10 days.

Within a commercial operation, synchronization of oestrus within abreeding herd is important from both an economic and herd managementperspective. It is difficult to detect accurately the time at whicheither natural or artificial insemination (AI) of a sow populationshould occur if weaned sows are exhibiting oestrus at different timesand/or individual sows within a population do not exhibit oestrus. Thiscan result in low efficiency, particularly in preparing liquid boarsemen for AI. Without limiting the present invention to any one theoryor mode of action, decreasing the weaning to oestrus interval and/orincreasing the number of sows within a population which exhibit oestrusallows for more efficient management of pig production. Furthermore, andalso without limiting the present invention in any way, decreasing theweaning to oestrus interval means that insemination, either natural orartificial, can take place at an earlier time period and result in anincreased number of progeny pigs weaned per sow/year and/or sowpopulation/year.

The skilled person would clearly understand that reference to naturalinsemination is reference to a natural mating of the sow with a boar,while reference to artificial insemination is reference to inseminationof the sow with boar semen by artificial means, which means could be anymeans known within in art.

Accordingly in a further aspect the invention provides a method ofimproving the reproductive performance of a sow population comprisingthe steps of:

-   -   (i) administering an effective amount of a β-agonist to a sow        population during lactation such that the sow population        exhibits a decreased weaning to oestrus interval compared to a        sow population which has not been administered the β-agonist;        and    -   (ii) inseminating sows in said sow population which exhibit        oestrus.

Also without limiting the present invention to any one theory or mode ofaction, the present inventors have determined that administration of theβ-agonist ractopamine during lactation increases or maintains the numberof progeny pigs weaned per sow and/or sow population in subsequentpregnancies.

Accordingly, in another aspect the present invention is directed to amethod of increasing or maintaining the number of progeny pigs weanedper sow in subsequent pregnancies comprising administering an effectiveamount of a β-agonist during lactation.

In another aspect the present invention is directed to a method ofincreasing or maintaining the number of progeny pigs weaned per sowpopulation in subsequent pregnancies comprising administering aneffective amount of a β-agonist during lactation, to each sow withinsaid population.

Preferably, said β-agonist is ractopamine.

As detailed hereinbefore, the applicants have determined thatadministration of the β-agonist ractopamine to lactating sows increasesor maintains reproductive performance. The pharmacological activity ofβ-agonists like ractopamine is to activate adrenergic beta-receptors.Without limiting the present invention to any one theory or mode ofaction, activation of adrenergic beta-receptors leads to increasedintracellular concentration of cyclic adenosine monophosphate (cAMP),which triggers various events in various cells and organs. Cellularresponses to beta-receptor activation include for example lipolyticactivity in adipose tissues, smooth muscle relaxant activity in thebronchi and increased frequency of contractions in the heart.Accordingly, in the context of the present invention, while ractopamineis the preferred β-agonist and preferably in the form of ractopaminehydrochloride. It will also be understood by the skilled person that anyβ-agonist which exhibits the same properties as ractopamine could beused. For example and without limiting the present invention in any way,other β-agonists which may be used include salmeterol, formoterol,bambuterol, clenbuterol and/or derivatives thereof.

The chemical structures of some β-agonists comprise at least oneasymmetric carbon atom, and such drugs commonly exist in opticallyactive isomeric form, with the chiral carbon atom having (R) or (S)configuration. Compounds with two chiral centres, such as ractopamine,have four isomers, which are the RR-, SS-, RS-, and SR-isomers.Accordingly, it should be understood that reference to a β-agonist, forexample ractopamine, in the context of the present invention isreference to a mixture of 1 or more of the isomers of said β-agonist.Preferrably, the β-agonist is ractopamine and is a mixture of all fourisomers of ractopamine in approximately similar concentrations (i.e.,the racemate).

The terms “β-agonist”, “ractopamine” or “isomer” as used herein refernot only to the free base, but also to acid addition salts or solvatesthereof. Acid addition salts include, for example addition saltsprepared with various acids, for example, hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, nitric acid, or organic acids,such as citric acid, fumaric acid, tartaric acid, acetic acid, maleicacid, benzoic acid, p-toluenesulphonic acid, methanesulphonic acid, andthe like. In relation to orally administrable forms, such as in a feedcomposition or premix, preferably the ractopamine is the hydrochloridesalt form. Hydrate forms and polymorphs are also included in the presentinvention; particularly forms that can be manufactured as dry powder orforms that are water-soluble. Reference is made to Merck Index 11thedition (1989) items 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142,2347, 7765, 1840, 9720, 7461, 1317, 4159, and 963 and references citedtherein and, to Am. Rev. Resp. Dis. 1988, 137: (4; 2/2) 32.

As used herein, the term “effective amount” or the like refers to anamount of a β-agonist, such as, for example ractopamine, that issufficient to obtain a sufficient, sought-after, expected or wantedbeneficial effect. In the context of the present invention and withregard to sows, a sufficient beneficial effect is considered to bepresent, if an increase or maintenance of reproductive performance asherein before defined is achieved. Preferably, said reproductiveperformance is an increase or maintenance of ovarian function. Morepreferably, said reproductive performance is an increase or maintenanceof the number of sows which return to oestrus within a sow population.Preferably, said reproductive performance is a decrease in the weaningto oestrus interval of a sow and/or sow population. In another preferredembodiment, said reproductive performance is an increase or maintenanceof the number of pigs weaned/sow and/or sow population.

As will be realised by those skilled in the art, the amount of β-agonistadministered will depend on the duration of the treatment and numerousother factors as, for example, but not limited to, the weight of theindividual sow, age of the sow and the chosen administration regime, aswell as the form in which it is administered, this amount being easilydetermined by the person skilled in the art by routine methods. It isexpected that the amount will fall into a relatively broad range thatcan be determined by routine trials.

In general, the doses of the ractopamine to be administered to sows mayas an example be 5 to 200 mg/animal/day. It is common and it may befound advantageous to change the feed inclusion of ractopamine duringthe treatment period and all changes in the doses administered to theanimals will of course influence the total consumption per animal ofactive ingredient. In the present method, ractopamine can beadministered by any suitable means, including parenterally,transdermally, subcutaneously, intravenously, intramuscularly, orally,topically, nasally, rectally, by inhalation or via implanted reservoirsor pellets containing the drug. A preferred route of administration isthe oral route, with the drug mixed into the feed or the drinking waterof animals.

Accordingly, another aspect of the present invention relates to feedcompositions including an admixture of feed materials containingractopamine. Such an admixture is preferably in the form of a premixcomprising ractopamine and other components, the determination of whichwould be well within the capabilities of the person skilled in the art.Said premix is preferentially administered in the feed to animals thatare being given a diet, consisting of protein-containing food materials.

Accordingly, in another embodiment, the invention provides a premixincluding ractopamine, said premix being capable of increasing ormaintaining reproductive performance. The amount of ractopamine will begenerally chosen to provide from a total of about 5 to about 200 mg ofractopamine/animal/day. Preferrably, the amount of ractopamineadministered is between 5 to about 10 mg of ractopamine/animal/day.

A commercially available formulation of ractopamine is PAYLEAN® (Elanco)which comes as a solid dry premix comprising 20 g/kg of ractopaminehydrochloride with ground corncobs. Without limiting the presentinvention in any way, for feeding to sows, the dry premix is typicallythoroughly mixed by the consumer into appropriate solid feed ingredientsto obtain ractopamine hydrochloride amounts of 9-18 grams/ton.Accordingly, in a preferred embodiment of the invention, the premix ofractopamine is PAYLEAN®.

Diluents suitable for use to make up the feed compositions may includethe following: alfalfa meal, soybean meal, cottonseed oil meal, linseedoil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal,corncob meal, rice kernel and the like.

Since ractopamine is chemically stable in water, in an alternativeembodiment the ractopamine may be administered in the drinking water. Inthis case, said premix of ractopamine can be prepared, containing afixed concentration of ractopamine in a dry, water-soluble carrier or ina suitable volume of a fluid, such as water, which, in turn, can beadded to the drinking water of the animals, by adding said premix volumedirectly to the drinking water of the animal or by adding said premix toan automatic drinking system for animals.

Formulations for oral use of ractopamine may also be presented aschewing tablets, or as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin, or olive oil. Tablets may beuncoated or they may be coated using known techniques, optionally tomask taste, delay disintegration and delay absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period of time, such as for examples one or more days. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed.

As hereinbefore described, the β-agonist, preferably ractopamine, may bein the form of a premix. Such premix may take the form of powders,dispersible powders or granules suitable for preparation of an aqueoussuspension by addition of water, or for the addition to a feedcomposition. Formulation as a suspension provides the active ingredientin admixture with a dispersing or wetting agent, suspending agent andone or more preservatives. Suitable dispersing or wetting agents are,for example, naturally-occurring phosphatides, as e.g., lecithin, orcondensation products of ethylene oxide with e.g., a fatty acid, a longchain aliphatic alcohol or a partial ester derived from fatty acids anda hexitol or a hexitol anhydride, for example, polyoxyethylene stearate,polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitanmonooleate, etc. Suitable suspending agents are, for example, sodiumcarboxymethylcellulose, methylcellulose, sodium alginate, etc.

Additionally, other preferred forms of administration are by inhalationor by transdermal delivery systems or subcutaneous delivery systems,which will reduce or avoid gastrointestinal metabolism and hepaticfirst-pass metabolism by metabolising enzymes; such delivery systems maybe designed to prolong the absorption or decrease the peak plasma drugconcentration or to increase the exposure of the animal to the drug(increased AUC, meaning Area Under a Curve, where plasma drugconcentration has been plotted over time).

Preparations of ractopamine may also be administered parenterally(intravenous, intramuscular, subcutaneous or the like) in dosage formsor formulations containing conventional, non-toxic pharmaceuticallyacceptable carriers and adjuvants. The formulation and preparation ofsuch compositions is well known to those skilled in the art ofpharmaceutical formulations. For parenteral administration ractopaminepreparations may also be prepared in the form of a paste or pellet andadministered as an implant.

As an alternative to a paste, pellet or subcutaneous implant, parenteraladministration may involve injection of a solution, containingsufficient amount of ractopamine to provide the animal with 5 to 200mg/day of the active ingredient.

In the methods of the present invention, the skilled person would bewell aware that the β-agonist can be administered together with one ormore other active compound(s). Compounds that improve or prolong thetherapeutic effect of β-agonists, e.g. compounds that delay or inhibitthe absorption or the metabolic degradation of the compound, may also beco-administered with the β-agonist to further improve the therapeuticactivity. Other drugs such as for example other growth promoting agentsand antibacterial compounds or immuno-stimulating compounds may becombined with the selected drug of the present invention to obtainimproved health of the animal or improved activity of the formulation.It should be understood that supplementary ingredients could also beincorporated into the β-agonist preparations, the determination of whichwould be well within the capabilities of the person skilled in the art.

The base diet of the present invention can be any typical pig diet knownin the art, but will preferrably be those specially formulated forlactating sows.

In formulating the diets for lactating sows, a person of skill in theart can use the general knowledge in the art. For example, the NutrientRequirements of Swine Nutrient Requirements of Domestic Animals, Number3, 9^(th) rev. ed. (National Academy of Science, Washington, D.C.:1988), can be consulted to determine the amino acids, mineral elements,vitamins, and other dietary requirements for sows as a function ofweight. The diet can contain between 5 and 30% by weight crude proteinand be formulated for the specific use as a lactation diet. For example,an exemplary lactating sow diet may contain from about 600 to about 1800g/hd/day of crude protein, from about 30 to about 70 g/hd/day of lysine,from about 35 to about 55 g/hd/day of calcium, and from about 30 toabout 50 g/hd/day of phosphorus.

A further example of recommended daily nutrient levels during lactationexpressed in grams per head per day, except where noted otherwise, isshown in Table 1.

TABLE 1 COMPONENT LACTATION Crude Protein 899 Lysine 44 Tryptophan 11Threonine 32 Minerals Calcium 48 Phosphorus 43 Salt 27 Copper, mg 90Iodine, mg 1.6 Iron, mg 900 Manganese, mg 216 Selenium, mg .54 ^(b)Zinc, mg 900 Vitamins Vitamin A, IU 60,000 Vitamin D, IU 9,000 VitaminE, IU 240 Vitamin K, ^(c) mg 24 Riboflavin, mg 45 Niacin, mg 270d-Pantothenic Acid, mg 156 Vitamin B₁₂ , Mg .18 Folic Acid, mg 9 Biotin,mg 1.2 Choline, mg 3,000 ^(a) Legal addition if fed 1.8 kg/hd/day. ^(b)Assumes at least 5.4 kg/day feed intake of a diet containing .80%lysine. ^(c) Menadione sodium bisulfite (MSB) or equivalent.

The skilled person would be well aware that other feed components may beadded to the lactation diet, for example, but not limited to, milo orcorn, soybean meal, monocalcium phosphate, Limestone, salt, vitamins,Trace minerals, selenium. The feed schedule and feed rates used with thepresent method can be any standard schedule and rate used in the art.Generally, lactating sows are generally fed from about 3 to about 7 kgof the diet per day, and preferably from about 5.5 to about 6.5 kg perday. Generally, the feed is administered from 1 to 2 and up to 4 times aday. Accordingly, reference to a unit of diet in the context of thepresent invention should be understood as reference to the amount ofβ-agonist included in the average daily feed intake of a sow.

Without limiting the present invention to any one theory or mode ofaction the present inventors have determined that administration to asow of 10 ppm of ractopamine/unit of diet from day 1-13 of lactationfollowed by administration of 20 ppm of ractopamine/unit of diet fromday 14 of lactation until weaning, increases or maintains reproductiveperformance as herein before defined.

Accordingly, yet another aspect of the present invention is directed toa method for increasing or maintaining the reproductive performance of asow and/or sow population, the method comprising the steps of:

-   -   (i) administering to a sow 10 ppm of ractopamine/unit of diet        from day 1 to day 13 of lactation; and    -   (ii) administering to a sow 20 ppm of ractopamine/unit of diet        from day 14 of lactation until weaning.

In a preferred embodiment, said reproductive performance is an increaseor maintenance of ovarian function. More preferably, said reproductiveperformance is an increase or maintenance of the number of sows whichreturn to oestrus within a sow population. Preferably, said reproductiveperformance is a decrease in the weaning to oestrus interval of a sowand/or sow population. Preferably, said reproductive performance is anincrease or maintenance of the number of progeny pigs weaned per sowand/or sow population.

The term “ppm” refers to parts per million, more specifically to “gramsper kilogram” and 10 ppm equals 0.01 gram of ractopamine per kilogram offood material.

The invention will now be described with reference to the followingexamples which are intended only for the purpose of illustrating certainembodiments of the invention and are not to be taken as limiting thegenerality of the invention previously described.

EXAMPLES Example 1 Supplementary Ractopamine During Lactation ReducesSow Weight Loss and Improves Reproductive Performance

Sixty large white first parity sows were allocated to one of twotreatment groups (n=30 sows/treatment). One group (CONT) received astandard lactation diet (0.71 g available lysine/MJ digestible energy(DE)) throughout lactation, whilst the other group (RAC) received thestandard lactation diet supplemented with ractopamine at 10 ppm from d1-13 of lactation and 20 ppm from d 14 of lactation until mating. Theamount of feed offered each day was stepped up gradually, reaching 5kg/day by d 4 of lactation, and maintained at this level for the rest oflactation. Sows were weighed and P2 backfat measured on d 1, 14 and 20of lactation, the litter size standardised to 9 piglets within 24 hoursof lactation. Sows were weaned on d 21 of lactation, with boar exposurecommencing 4 d after weaning and sows artificially inseminated twice attheir first oestrus post-weaning. Subsequent reproductive performance ofall sows was recorded: weaning-to-oestrus interval (WOI) and secondlitter size. Sows failing to express eostrus within 10 d of weaning weredeemed to be anoestrus and allocated a nominal weaning-to-oestrusinterval of 15 d. A general analysis of variance model was used to studythe effects of RAC supplementation on sow weight loss during lactationand subsequent reproductive performance.

On d 1 of lactation, sow liveweight and P2 backfat were 177.7±2.8 kg and21.2±1.2 mm, respectively. RAC supplementation significantly decreased(P<0.05) liveweight loss between d 15 and 20 of lactation, tended(P<0.1) to reduce P2 backfat loss over the whole lactation, andincreased piglets born alive at the second litter (Table 2). A numericaldecrease in WOI (6.4±0.63 vs. 7.5±0.80) and the proportion of sowsexhibiting oestrus within 10 d of weaning (0.95±0.08 vs 0.75±0.08) wasobserved for RAC compared to CONT sows.

TABLE 2 Effect of dietary ractopamine during lactation on sow feedintake, liveweight and P2 backfat loss, and the number of piglets bornat the subsequent (second) litter Daily feed intake Lactation weightloss (kg) P2 backfat Piglets born at second litter Diet (kg/day) Days1-14 Days 15-20 loss (mm) Total born Born alive CONT 5.0 ± 0.14 7.2 ±1.33  4.3 ± 0./90^(b) 3.7 ± 0.55 8.5 ± 0.80 8.1 ± 0.74 RAC 4.9 ± 0.144.6 ± 1.41 1.3 ± 0.96^(a) 2.3 ± 0.57 9.7 ± 0.54 9.5 ± 0.52 ^(ab)Means ina column with different superscripts differ significantly (P < 0.05);CONT, control; RAC, ractopamine.

Example 2 Effect of Paylean Treatment During First Lactation on MaternalMuscle Catabolism and Post-Weaning Fertility

This experiment was conducted at the University of Adelaide's Pig andPoultry Production Institute (PPPI) at Roseworthy, South Australia, withapproval from the animal ethics committees of Primary Industries andResources South Australia and The University of Adelaide. The experimentused sixty Large White/Landrace parity 1 sows, and was conducted in fourreplicates: replicates one and two were run in October and November2006, respectively (spring); and replicates three and four were run inMarch and April 2007, respectively (autumn).

At entry into the farrowing shed, Sixty Large White/Landrace firstparity sows were weighed, and P2 backfat and maximum eye muscle depth(MMD) measured. Sows were then stratified according to both liveweightand body composition and allocated to one of two treatment groups (n=30sows). One group (Control) received a standard lactation diet (0.71 gavail. lys/MJ DE) throughout lactation, whilst the other group(Ractopamine) received the same standard lactation diet but supplementedwith ractopamine at 10 parts per million (ppm) from days 1-13 oflactation and 20 ppm from day 14 of lactation until mating. Dietarytreatments commenced on day 1 of lactation (Day 0=first 24 hours afterfarrowing). During lactation, the amount of feed offered each day wasstepped up gradually, reaching 6 kg/day by day 7 of lactation, and wasfed over three meals per day, with daily feed disappearance recorded foreach sow. Weaning took place 21 days after farrowing, and betweenweaning and first Al sows received 3 kg/day of their respective diets.Sows were weighed, and P2 backfat and MMD measured on days 1, 7, 14 and20 of lactation. Gilts were weighed prior to being fed, and P2 backfatand MMD were measured over the last rib 65 mm down from the vertebrae byan experienced commercial operator using a 3.5 MHz linear probe(Ausonics Impact). Litter size was standardised to 9 piglets within 24hours of farrowing, with piglets receiving only maternal milk as theirfeed source and weighed on days 1, 7, 13 and 20 of their mother'slactation. Maternal milk samples were collected on days 3, 13 and 20 oflactation and analysed for fat and protein content.

After weaning, sows were housed in groups of three or four. Boarexposure commenced on the fourth day after weaning, consisted of 15minutes of full, physical boar contact and was conducted in a detectionmating area (DMA). At their first oestrus after weaning, sows twoartificial inseminations (AIs), 24 hours apart.

All Als took place in the DMA, with fence-line contact with a boarduring the procedure. Inseminations were performed as per standardindustry practice using disposable spirette catheters, with eachinsemination consisting of an 80 ml dose of fresh, extended semen (3×10⁹spermatozoa per inseminate; <4 days old). Semen used for this experimentwas purchased from a commercial artificial insemination collectioncentre (SABOR Pty. Ltd, Clare, South Australia). Sows not detected inoestrus by 10 days after weaning were described as anoestrous.

Results Sow Live Weight, P2 Backfat and MMD

Live weight, P2 backfat and MMD on day 1 of lactation were the same forthe Control and Ractopamine treatments: 176.4±2.82 and 180.0±3.00 kg,21.5±0.54 and 20.9±0.70 mm, and 55.5±0.86 and 56.8±0.77 mm,respectively. Live weight loss between days 1-7 and days 8 to 14 oflactation was similar for Control and Ractopamine sows; however,Ractopamine sows lost significantly less (P<0.05) live weight betweendays 15 and 20 of lactation (Table 3). Although the reduction in MMD inlactation was similar for the Control and Ractopamine treatments,Ractopamine sows lost significantly less (P<0.05) P2 backfat compared toControl sows (Table 3).

Reproductive Performance

Weaning-to-oestrus interval (WEI) was similar for Control andRactopamine sows. However, there was a numerical, but not significant,reduction in the proportion of Control compared to Ractopamine sowsexhibiting oestrus within 10 days of weaning (Table 3). A numerical, butnot significant, increase (P=0.155) in the total number of piglets bornat the second litter was observed for Ractopamine compared to Controlsows (Table 3). However, there was a tendency (P=0.064) for the numberof piglets born alive-at the second litter to be higher for Ractopaminecompared to Control sows (Table 3).

Piglet Growth Characteristics

Individual piglet live weight gain between days 1 and 7 of lactation wasunaffected by maternal dietary treatment (Table 4). However, averagedaily live weight gain (ADG) between days 7 and 14 of lactation tended(P<0.1) to be lower for piglets suckling Ractopamine sows compared toControl sows, while ADG between days 14 and 20 of lactation wassignificantly (P<0.01) lower for piglets suckling Ractopamine sowscompared to piglets suckling Control sows (Table 4).

TABLE 3 Live weight, P2 backfat and MMD loss during lactation,weaning-to- oestrus interval (WEI), the proportion of sows exhibitingoestrous and second litter size for Control and Ractopamine sows PooledControl Ractoparnine SEM Liveweight loss in lactation (kg) Days 1-7 2.612.43 0.82 Days 8-14 4.69 2.98 0.83 Days 15-20 3.63^(a) 0.66^(b) 0.68 P2backfat loss in lactation (mm) 3.85^(a) 2.44^(b) 0.46 MMD loss inlactation (mm) 2.7 2.1 0.74 Weaning-to-oestrus (d) 7.51 6.39 0.74Proportion sows exhibiting oestrus* 0.75 0.95 0.08 Proportion mated sowspregnant 0.95 0.91 0.06 2^(nd) litter size: Total born 8.53 9.66 0.55Born alive 8.11** 9.48** 0.51 ^(ab)superscripts within row indicatesignificant difference; P < 0.05. **P = 0.064 *Sow not exhibitingoestrus within 10 days of weaning were assigned a nominalweaning-oestrus of 15 days

TABLE 4 Average daily live weight gain (ADG) of piglets suckling Controland Ractopamine sows ADG (kg/d) Control Ractopamine Pooled SEM Days 1-70.2  0.2  0.004 Days 8-14 0.25* 0.24* 0.005 Days 15-20 0.30^(a )0.26^(b ) 0.008 ^(ab) superscripts within row indicate significantdifference; P < 0.05. *P < 0.1

TABLE 5 Milk fat and protein on days 3, 13 and 20 of lactation forControl and Ractopamine sows Day of Milk fat (g/l) Milk protein (g/l)lactation Cont. Ract. Pooled** Cont. Ract. Pooled** 3 69.2^(b) 80.4^(c) 74.8^(d) 45.2 45.7  45.5^(d) 13 65.7^(a) 64.7^(a)  65.2^(c) 41.6 39 40.3^(c) 20 66.1^(a) 65.8^(a)  65.9^(c) 41.5 39.9  40.7^(c) Pooled67.0* 70.3*  42.8^(†)  41.5^(g) across day Pooled SEM 2.18 0.72^(ab)indicates significant interaction between day of lactation anddietary treatment; P < 0.05 ^(fg) within row indicates significantdifference between dietary treatments; P < 0.05. * P = 0.064 ^(cd)withincolumn indicates significant differences between days of lactation; P <0.05

Milk Composition

The protein content of milk was significantly lower for Ractopaminecompared to Control sows (Table 5). Similarly the fat content of milkcollected from Ractopamine sows tended (P=0.064) to be higher than inmilk obtained from Control sows (Table 5). Day of lactationsignificantly affected milk protein and fat content (Table 5), with bothfat and protein content significantly higher on day 3 of lactationcompared to days 13 and 20.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications which fall within thespirit and scope. The invention also includes all of the steps,features, compositions and compounds referred to or indicated in thisspecification, individually or collectively, and any and al combinationsof any two or more of said steps or features.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

1. A method of increasing or maintaining the reproductive performance ofa sow or sow population comprising administering an effective amount ofa β-agonist during lactation. 2-20. (canceled)
 21. A method forsynchronizing mating and/or artificial insemination of a sow populationcomprising administering an effective amount of a β-agonist duringlactation, to each sow within said population.
 22. (canceled)
 23. Amethod for increasing the number of sows within a sow population whichundergo mating and/or artificial insemination comprising administeringan effective amount of a β-agonist during lactation, to each sow withinsaid population. 24-26. (canceled)
 27. A feed composition comprising aneffective amount of a β-agonist wherein said effective amount increasesor maintains the reproductive performance of a sow. 28.-29. (canceled)30. The method according to claim 1, wherein said reproductiveperformance is ovarian function.
 31. The method according to claim 1,wherein said increase or maintenance of reproductive performance is adecrease in the weaning to oestrus interval of a sow.
 32. The methodaccording to claim 1 wherein said increase or maintenance ofreproductive performance is an increase or maintenance of the number ofsows in a population which return to oestrus at weaning.
 33. The methodaccording to claim 1, wherein said increase or maintenance ofreproductive performance is an increase or maintenance of the number ofprogeny pigs weaned per sow in subsequent pregnancies.
 34. The methodaccording to claim 1 comprising supplementing the lactation diet with aneffective amount of a β-agonist from day 1 of lactation until weaning.35. The method according to claim 1 comprising supplementing thelactation diet with an effective amount of a β-agonist from day 1 oflactation until weaning, wherein the lactation diet is supplemented withbetween 5 and 20 ppm of β-agonist/unit of diet.
 36. The method accordingto claim 1 comprising supplementing the lactation diet with an effectiveamount of a β-agonist from day 1 of lactation until weaning, wherein thelactation diet is supplemented with 10 ppm of β-agonist/unit of dietfrom days 1 to 13 of lactation and 20 ppm of β-agonist/unit of diet fromday 14 of lactation until weaning.
 37. The method according to claim 1wherein said method comprises the steps of: (i) administering aneffective amount of a β-agonist to a sow population during lactationsuch that the sow population exhibits a decreased weaning to oestrusinterval compared to a sow population which has not been administeredthe β-agonist; and (ii) inseminating sows in said sow population whichexhibit oestrus.
 38. The method according to claim 1 wherein theβ-agonist is ractopamine.
 39. The method according to claim 21 whereinsaid β-agonist is ractopamine.
 40. The method according to claim 23wherein said β-agonist is ractopamine.
 41. The method according to claim23 wherein the number of times a sow and/or sow population undergoesmating and/or artificial insemination per year is increased.